AMG 701 is an anti–B-cell maturation antigen (BCMA) half-life extended bispecific T-cell engager (BiTE) molecule in phase 1 development for relapsed/refractory multiple myeloma (RRMM). The primary objective of this phase 1 first-in-human study was to investigate the safety and tolerability of AMG 701 and determine a biologically active dose; secondary objectives included pharmacokinetic (PK) characterization, antimyeloma activity by International Myeloma Working Group criteria, and duration of response.
The study enrolled patients with multiple myeloma who either relapsed and/or were refractory or intolerant to ≥3 prior lines of therapy, including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), or an anti-CD38 antibody. Intravenous AMG 701 infusions were administered weekly in 4-week cycles until progressive disease (PD), adverse event (AE), death, or consent withdrawal. In an attempt to prevent severe cytokine release syndrome (CRS), a step dose of 0.8 mg was administered before target doses ≥1.2 mg. By day 8, the target dose was reached. Doses of 5 μg to 45 μg were administered to 1 patient in each of the first 3 cohorts, doses of 0.14 mg to 1.2 mg were administered to 3 to 4 patients each in the next cohorts, and doses of 1.6 mg to 12 mg were administered to 3 to 10 patients each in subsequent cohorts.
Among 85 patients who received AMG 701, the median age was 64 years and the median time since diagnosis was 5.6 years; 25% had extramedullary disease, and 80% had received prior autologous stem-cell transplantation. The median number of prior regimens was 6, with 93% of patients having received a prior anti-CD38 antibody; 62% were triple refractory to a PI, an IMiD, and an anti-CD38 antibody. A total of 64 patients discontinued, primarily because of PD (80%), AEs (8%), and withdrawal of consent (6%). Median treatment duration was 7.6 weeks, and median follow-up was 6.5 months (for responders).
Anemia (42%), neutropenia (25%), and thrombocytopenia (21%) were the most common hematologic AEs, whereas CRS (65%), diarrhea (31%), hypophosphatemia (31%), fatigue (25%), and fever (25%) were the most common nonhematologic AEs. Most CRS events were grade 1/2 (n = 23 and n = 24, respectively), and grade 3 CRS events (n = 8) were reversible with corticosteroids and tocilizumab within a median of 2 days. Other dose-limiting toxicities were transient grade 3 atrial fibrillation, transient grade 3 acidosis, and grade 4 thrombocytopenia (1 each). Thirty-two patients (38%) experienced serious AEs, including infections (n = 14), CRS (n = 8), and asymptomatic pancreatic enzyme increase (n = 3). Four deaths occurred, but none was considered related to the study drug. Reversible treatment-related neurotoxicity occurred in 6 patients, lasted a median of 1 day, and was associated with CRS in 4 of these 6 patients.
An overall response rate (ORR) of 26% (21/82 evaluable patients) was observed, along with a rate of very good partial response or better (≥VGPR) of 17% (14/82). In the most recent evaluable cohort (n = 6), ORR was 83%; notably, 4 of 5 of these responders were triple refractory and 1 patient experienced grade 3 CRS. Overall, the following responses were observed: stringent complete response (CR), 5 (3 minimal residual disease [MRD] negative, 2 currently MRD undetermined); MRD-negative CR, 3; VGPR, 6; partial response, 7. The median time to response was 1.0 month, time to best response was 2.8 months, and interim median response duration was 5.6 months, with responses ongoing in 17/21 patients when last assessed, including a single patient who showed response at 22 months. A favorable PK profile was observed.
Results from this study of AMG 701 showed acceptable safety, promising efficacy, and a favorable PK profile in heavily pretreated patients with RRMM, thereby supporting ongoing evaluation and further clinical development of this agent.
Abstract 181. ASH 2020. December 5, 2020. A Phase 1 First in Human (FIH) Study of AMG 701, an Anti-B-Cell Maturation Antigen (BCMA) Half-Life Extended (HLE) BiTE® (bispecific T-cell engager) Molecule, in Relapsed/Refractory (RR) Multiple Myeloma (MM).